The pharmaceutical compositions which have been used as gastric antisecretory and antispasmodic agents have been such as atropine, homatropine, propantheline bromide, dicylomine hydrochloride, and other compounds which are structurally dissimilar to the amidinoureas. Due to the anticholinergic properties of these compounds, they are known to produce undesirable side effects such as mydriasis, xerostomia, cyclopegia, and other unwanted effects.
The narcotic analgesics remain the drugs of choice for treatment of diarrhea and dysentery. This group of drugs, however, has serious disadvantages. They possess the narcotic properties of producing sleep as well as analgesia. They also have physical and psychological dependence liabilities. Morphine and codeine remain two outstanding examples of this group.
In 1957 a meperidine derivative, diphenoxylate, was introduced into the therapeutic regimen of diarrhea control. This agent possesses morphine-like as well as anticholinergic properties, both of which may be responsible for its antidiarrheal actions. Diphenoxylate, because of its narcotic properties, is capable of supporting morphine physical dependence in the monkey. Overdoses in children can lead to symptoms and fatalities that are characteristic of the narcotics, e.g., respiratory depression and reversal of morbidity with nalorphine.
Since pharmaceutical compositions other than those containing the phenylamidinoureas which have been useful in the treatment of ulcers, diarrhea, dysentery and spasms unfortunately exhibit undesirable side effects, it is desirable to find classes of compounds with minimal side effects.
Recently, a new class of phenylamidinoureas and their uses as antisecretory, antispasmodic, anti-ulcerogenic, anesthetic and antidiarrheal agents have been reported in Arzneimittel Forschung (Drug Research) 28(11), 1433-1480 (1978), and U.S. Pat. Nos. 4,058,557, 4,060,635, 4,088,785, 4,115,564, 4,117,165, 4,147,804, 4,150,154, 4,169,155 and 4,178,387. Their use in the treatment of dysmenorrhea has also been reported in copending application Ser. No. 26,281, as well as their use in the treatment of hypertension in copending application Ser. No. 26,161. Additionally, the phenylamidinoureas are known to be effective agents against protozoal infections.
Parasitic protozoal infections are difficult to eradiate in human or livestock populations. The population of insect carriers in temperate and tropical areas of the world creates a constantly renewing reservoir of infection. Furthermore, the armament of drugs utilized to inhibit and suppress the proliferation of these parasites gradually loses its efficacy due to the evolution of resistant protozoal strains. A complete cure of the infected hosts is still more difficult due to the multi-stage character of the protozoal life cycle.
The chemotherapeutic agents utilized in treatment of human malaria appear to act in one of two ways. The first proposed mechanism responsible for the action of the oldest known antimalarial agent, quinine, is that of nonspecific DNA binding or intercalation. The second proposed mechanism is specific to protozoal diseases and presumably inhibits protozoal growth by enzyme antagonism.
Protozoa apparently cannot utilize preformed folate or folic acid in their metabolic cycles and require a supply of para-aminobenzoic acid in order to synthesize their own supply of folic acid. As a consequence, folic acid enzyme antagonists have been found to show antiprotozoal activity. Interference with the enzymatic machinery in this synthetic pathway may be responsible for the selective antiprotozoal action of this class of drugs. Drugs which act in this fashion include chloroguanide, cycloguanil pamoate, pyrimethamine and its derivatives, as well as sulfamides and sulfones.
Among the folic acid antagonists, the biguanide members may be, in some cases, transformed in the host body to form active triazine metabolites. However, the triazine metabolite of chloroguanide has little or no usefulness in the therapy of humans and monkeys due to its rapid excretion from the body. Moreover, this latter class of compounds, that is, folic acid inhibitors, are most susceptible to a loss of efficacy due to the appearance of therapeutically resistant strains of protozoa. In fact, P. berghei is known as a pyrimethamine-resistant protozoal strain. Structural changes in the triazine rings of the presumably active form of these antiprotozoal drugs, as well as its method of administration, may modify the activity unpredictably as well as alter the rate of excretion of the drug from the host body. For example, while in malaria cases chloroguanide is rapidly excreted from the body when in its triazine form and has little or no usefulness, chloroguanide triazine pamoate, when tested with P.-berghei-infected mice, has good and lasting effects with a single muscular injection and is nt excreted rapidly from the host body. Owing to such unpredictability and the limited drugs available for treatment of human and animal diseases caused by blood-residing parasites, there is need for effective drugs for use in the treatment of these diseases.
1-(N-alkylamidino)-3-phenylureas were investigated by Curd et al. in the late 1940's for antimalarial activity against the malarial parasite Plasmodium gallinaceum in chicks. 1-(N-alkylamidino)-3-(p-chlorophenyl)ureas showed only anti-erythrocytic activity at high doses while 1(N-phenylamidino)-3-alkylureas showed no antimalarial activity whatsoever (Curd, F. H. S. et al., J. Chem. Soc. 1949, 1732). 1-amidino-3-phenylureas were investigated by Urbanski in 1960. This study indicated that of a large class of 1-amidino-3-(monosubstituted phenyl)ureas, the highest activity against the malarial parasite Plasmodium gallinaceum in chicks was obtained with 1-amidino-3-(4-nitrophenyl)urea (Skowronska-Serafin, B. and Urbanski, T., Tetrahedron, 10, 12-25 (1960)).
U.S. Pat. No. 3,539,616 to Wall discloses that 1-amidino-3-(di- and trisubstituted phenyl)ureas exhibit anti-malarial activity. The preferred phenyl substituents consisted of halogen or cyano. 2,6-substitution of the phenyl group attached to the 3-position of the urea was not disclosed.
In fact, a more recent publication of Goodfood, Walls et al., Br. J. Pharmac. 48, 650-654 (1973), indicated that subtituents ortho (i.e., 2' or 6' substitution) to the urea side chain of the phenyl group would exhibit low anti-malarial activity.
The antiprotozoal uses of 1-(N-phenylamidino)-3-alkylureas and 1-amidino-3-phenylureas wherein the phenyl group is substituted at positions ortho to the urea side chain have been reported in U.S. Pat. No. 4,340,609.
1-phenyl-3-(N'-alkylamidino)thiourea compounds are known in the art. See Curd et al., J. Chem. Soc., p. 1732, 1739 (1949). A study in the 1940's by Curd of amidinothioureas resulted in a determination that they exhibit no antimalarial activity. However, it has now been found that novel classes of amidinothioureas possess valuable pharmaceutical properties.